1. Field of the Invention
The present invention relates to certain aminoalkyl naphthalenediol derivatives that enhance host resistance to infectious organisms which are administered prophylactically to individuals whose resistance to infections is compromised by chemotherapy, surgery, burns or other forms of severe stress.
2. Brief Description of Disclosures in the Art
Recent medical progress has resulted in beneficial therapy for many patients with conditions which were previously untreatable. As a result of both the extended survival of such patients and the therapeutic methods employed, today's physicians are more frequently encountering the patient who is at great risk of developing infection because his host defenses have been impaired. For example, infection is now the leading cause of death in both leukemia and lymphoma. Interference with host defense mechanisms has resulted in the frequent development of infections in this type of patient with organisms formerly considered nonpathogenic.
Over the past few decades, the host defense system has undergone intensive study, and it has become clear that this system involves several different but interacting resistance mechanisms. In addition, the ability to defend oneself against a specific pathogen can frequently be ascribed to a particular mechanism. Therefore, patients with discrete immunologic defects are frequently at risk for infection with a relatively limited number of pathogens. On the other hand, those with extensive host defense system dysfunction involving several different defense mechanisms, as might occur during intensive therapy of malignant diseases, are often at risk for infections with a bewildering array of potential pathogens. Since fairly specific and effective therapies are available for most of the pathogens encountered in this setting, the establishment of an etiologic diagnosis and beginning of the appropriate therapy of infection early are of utmost importance in the management of these patients.
It has been found that certain compounds including lipopolysaccharide, glucans, ubiquinones, bestatin, amphotericin B, tuftsin, thymic hormones, interferon, polyadenylic acid complexes, pyran copolymers, levamisole, methisoprinol and the like, although not specifically therapeutic for a particular pathogen, act in such a manner to improve the host resistance to infection by bacteria, virus, fungus, or parasite in a human host whose immunological system has been compromised.
In the past, bacterial cell wall products (e.g., BCG, C. parvum, etc.), as well as plant polysaccharides (e.g., lentinan, krestin, etc.), have been employed to stimulate the natural host resistance. These agents all suffer from undesirable toxic side effects, such as granulomatous inflammation, etc. Presumably the development of inflammation enhances the mobilization and activation of inflammatory cells as well as augmentation of the immune response (adjuvant effect).
In light of the above discussion, new classes of organic compounds are constantly being evaluated and screened to see if they possess host resistance enhancement activity.
One class of compounds recently of interest are the aminoalkyl naphthalenediols.
In the art, naphthalenediols are described in U.S. Pat. No. 3,009,912; British Pat. Nos. 790,203; 790,202; and in Brit. J. Pharmacol. 12(1957) p. 171, "Anti-Malarial Activity of Hydroxy-Substituted Naphthalene Compounds" by W. M. Duffin and I. M. Rollo. The above compounds are described as being active as antimalarial agents against blood forms of plasmodium species. However, there is no specific suggestion as to their use as host resistance enhancement agents.
At present, there is no effective host resistance enhancer on the market that does not possess the ability to cause intense granulomatous inflammation. The use of host resistance compounds that cause inflammation is not desirable.
For reviews, see (1) J. Kralovec, "Synthetic Immunostimulants in Antitumor Therapy," Drugs of the Future 8(1983)615; (2) J. W. Hadden, "Immunomodulators in the Immunotherapy of Cancer and Other Diseases," Trends in Pharmacological Sciences, (1982)191; (3) E. Arrigoni-Martelli, "Developments in Drugs Enhancing the Immune Response," Meth. Find. Exptl. Clin. Pharmacol, 3(1981)247; and (4) J. Drews, "The Experimental and Clinical Use of Immunomodulating Drugs in the Prophylaxis and Treatment of Infections," Infection, 12(1984)157.
Therefore, it is an object of this invention to provide host resistance enhancement agents that are safe, effective and whose therapeutic mechanism does not involve significant granulomatous inflammation.
Further, it is an object of this invention to provide a pharmaceutical composition for host resistance enhancement including said agent and an acceptable pharmaceutical carrier thereof.
Furthermore, it is also an object of this invention to provide a method of treatment for enhancing host resistance in humans who are immunologically compromised.